Fluoxetine (Prozac) is a commonly prescribed antidepressant that targets the serotonin transporter. Unlike tricyclics, such as imipramine, fluoxetine has little effect on other receptors, resulting in a lower occurrence of sedative and cardiovascular side effects. The semi-rigid sertraline (Zoloft) has a mechanism similar to fluoxetine, but is superior, because it confers lesser sedation than fluoxetine, in addition to being short acting. The primary objective of the present study is the design and synthesis of conformationally-restricted derivatives of fluoxetine, as potential pharmacologically active compounds. Both (R) and (S)-fluoxetine are flexible molecules. The (S)-isomer displays prolonged duration in man, which may contribute to side effects. Flexible molecules may have more than one site of action, with one preferred conformation at the receptor site. Side effects observed may be due to a low-energy conformation of fluoxetine at a second site. The synthesis of analogs in which the molecular framework of the pharmacophore is "locked" into semi-rigid form will allow a full study of the conformational aspects of drug action. The consideration of a benzazepine moiety in the proposed compounds was made in the light of cyclized version of norfluoxetine, which is active. Although amphetamines, cocaine and antidepressants profoundly affect human behavior, their underlyling mechanisms of action are unknown. It is postulated that the interactions of antidepressants with transporters account for the primary action of these drugs. The synthesized compounds will be used to study neurotransmitter uptake mechanisms, i.e. how transporters clear transmitters from the synaptic cleft after they are released from the nerve terminal. This part of the work will be done in colloboration with Dr. Louis J. DeFelice, Professor of Pharmacology and Neuroscience at Vanderbilt University School of Medicine. The research project will ultimately provide novel compounds for the treatment of depression and mental illness.